Bottom Line:
Accurate chromosome segregation depends on the proper attachment of sister kinetochores to microtubules emanating from opposite spindle poles.Merotelic kinetochore orientation is an error in which a single kinetochore is attached to microtubules emanating from both spindle poles.Despite correction mechanisms, merotelically attached kinetochores can persist until anaphase, causing chromatids to lag on the mitotic spindle and hindering their timely segregation.

fig0015: Multipolar spindle geometry promotes merotelic kinetochore attachments. (a) In normal unperturbed mitosis, sister kinetochores are attached amphitelically and segregate to opposite poles of the bipolar spindle during anaphase. (b) CIN cells with supernumerary centrosomes assemble multipolar spindles, which allows for the frequent formation of merotelic attachments. This is followed by the clustering of centrosomes into two poles and division in a bipolar fashion. During anaphase, merotelically attached kinetochores give rise to lagging chromosomes, which might lead to mis-segregation [5,6].

Mentions:
Recent studies showing that merotelic kinetochore orientation is the primary mechanism of CIN in cancer cells [4–7] have attracted wide attention. Understanding the mechanism of CIN is important because it can drive tumorigenesis through the tumor suppressor gene loss of heterozygosity and can promote tumor relapse [66–68]. Previous models have assumed that the chromosome mis-segregation phenotype of CIN cells resulted mainly from a defective SAC [69,70] or multipolar cell division [71]. However, recent studies have revealed that the SAC in many CIN cells is normal [7,72,73] and that progeny from multipolar divisions are usually inviable [5]. A recently proposed model for chromosome mis-segregation in CIN cells with supernumerary centrosomes suggested that multipolar spindles are assembled only transiently because of centrosome clustering before anaphase onset, and this allows for the frequent formation of merotelic attachments, but bipolar cell division. This model provides an elegant explanation for the high rates of lagging chromosomes observed in CIN cells (Figure 3). Although this mechanism does not rule out other factors contributing to CIN, it largely explains the chromosome mis-segregation typical of CIN cells and links it to centrosome amplification, another common feature of cancer cells. However, this model is based on analyses of CIN cell lines. Thus, it will be important to address whether this model can be extended to in vivo tumorigenesis models and identify the additional changes that allow CIN cells to tolerate aneuploidy. Although the relation between aneuploidy and tumorigenesis remains highly complex and controversial, a mounting body of evidence suggests that CIN contributes to tumor initiation and progression [74,75]. In this respect, it is encouraging that recent work showed that CIN can be suppressed in tumor cells [4]. It will also be interesting to further analyze the recently proposed model that merotelic attachments give rise to chromosome breakage at the centromere, which might activate DNA damage repair pathways and promote carcinogenesis [76]. However, it is important to mention that an independent study found no evidence of DNA damage on lagging chromosomes [77].

fig0015: Multipolar spindle geometry promotes merotelic kinetochore attachments. (a) In normal unperturbed mitosis, sister kinetochores are attached amphitelically and segregate to opposite poles of the bipolar spindle during anaphase. (b) CIN cells with supernumerary centrosomes assemble multipolar spindles, which allows for the frequent formation of merotelic attachments. This is followed by the clustering of centrosomes into two poles and division in a bipolar fashion. During anaphase, merotelically attached kinetochores give rise to lagging chromosomes, which might lead to mis-segregation [5,6].

Mentions:
Recent studies showing that merotelic kinetochore orientation is the primary mechanism of CIN in cancer cells [4–7] have attracted wide attention. Understanding the mechanism of CIN is important because it can drive tumorigenesis through the tumor suppressor gene loss of heterozygosity and can promote tumor relapse [66–68]. Previous models have assumed that the chromosome mis-segregation phenotype of CIN cells resulted mainly from a defective SAC [69,70] or multipolar cell division [71]. However, recent studies have revealed that the SAC in many CIN cells is normal [7,72,73] and that progeny from multipolar divisions are usually inviable [5]. A recently proposed model for chromosome mis-segregation in CIN cells with supernumerary centrosomes suggested that multipolar spindles are assembled only transiently because of centrosome clustering before anaphase onset, and this allows for the frequent formation of merotelic attachments, but bipolar cell division. This model provides an elegant explanation for the high rates of lagging chromosomes observed in CIN cells (Figure 3). Although this mechanism does not rule out other factors contributing to CIN, it largely explains the chromosome mis-segregation typical of CIN cells and links it to centrosome amplification, another common feature of cancer cells. However, this model is based on analyses of CIN cell lines. Thus, it will be important to address whether this model can be extended to in vivo tumorigenesis models and identify the additional changes that allow CIN cells to tolerate aneuploidy. Although the relation between aneuploidy and tumorigenesis remains highly complex and controversial, a mounting body of evidence suggests that CIN contributes to tumor initiation and progression [74,75]. In this respect, it is encouraging that recent work showed that CIN can be suppressed in tumor cells [4]. It will also be interesting to further analyze the recently proposed model that merotelic attachments give rise to chromosome breakage at the centromere, which might activate DNA damage repair pathways and promote carcinogenesis [76]. However, it is important to mention that an independent study found no evidence of DNA damage on lagging chromosomes [77].

Bottom Line:
Accurate chromosome segregation depends on the proper attachment of sister kinetochores to microtubules emanating from opposite spindle poles.Merotelic kinetochore orientation is an error in which a single kinetochore is attached to microtubules emanating from both spindle poles.Despite correction mechanisms, merotelically attached kinetochores can persist until anaphase, causing chromatids to lag on the mitotic spindle and hindering their timely segregation.